Cell cycle abnormality is a hallmark of cancer. Cyclin-dependent kinase (CDK) is a class of serine/threonine kinases that play a central role in the cell cycle, leading the activation, progression and end of the cell cycle. The CDK family includes CDK1-13.
CDK4/6 is over-active in many cancers, leading to cell proliferation out of control. Studies find that the overexpression of CyclinD1 and CDK4 may be involved in the occurrence of esophageal cancer, and the increased expression of both is related to the degree of differentiation of esophageal cancer. CDK4 is generally expressed in both benign and malignant pancreatic endocrine tumors. The expression of CDK4 in lung cancer tissues is also significantly higher than that in normal lung tissues. The degree of high positive expression is positively correlated with histopathological classification of lung cancer, lymphatic metastasis and clinical stage malignancy, which is a potential poor prognostic factor. CDK6 is also overexpressed in a variety of tumor cells, for example, CDK6 is detected to be overexpressed in male hormone-sensitive prostate cancer cell lines. And the exogenous overexpression of CDK6 leads to accelerated growth of tumor cell, while the growth rate of tumor cells interfered with CDK6 is significantly slower.
CDK4 and CDK6 have 71% homology to the amino acid composition, and this result suggests their functional similarity. Recent studies also reveal that CDK4/6-CyclinD can phosphorylate the transcription factor FOXM1, improving its stability and activity in melanoma. Thus, inhibition of CDK4/6 can achieve cell proliferation inhibition from downstream of the signaling pathway. The combination of CDK4/6 inhibitors and endocrine therapy can achieve a double inhibitory effect, and the preclinical study also confirms that the combination of CDK4/6 inhibitors and endocrine therapy has a significant synergistic effect.
CDK family inhibitors have received widespread attention as a potential target for tumor therapy over the past 20 years. However, the first generation of CDK inhibitors lacks selectivity and is a pan-inhibitor, such as flavopiridol which can inhibit CDK1, CDK2, CDK4, CDK6, CDK7 and CDK9. Although flavopiridol can induce cell cycle arrest, and show the role of cytotoxicity, clinical efficacy is unsatisfactory. The second generation of CDK inhibitors is designed to improve selectivity, in particular, selective inhibitors targeting CDK4/6 alone which show better clinical efficacy and less toxic side effects receive significant attention. Pfizer's CDK4/6 dual inhibitor Palbociclib (trade name Ibrance) became the first listed CDK4/6 dual inhibitor, and FDA has approved it as a first-line drug for the treatment of ER-positive, HER2-negative breast cancer.
Novartis's LEE011 is a CDK4/CDK6 dual inhibitor, which is most sensitive to malignant rhabdoid tumor and neuroblastoma. LEE011 is mainly combined with aromatase inhibitors and PI3K inhibitors, and can play a better anti-tumor activity in clinical trials. LEE011 combined with letrozole is used for the treatment of metastatic HR positive/HER2 negative breast cancer in clinical stage III. LEE011 combined with BYL719 and letrozole is used for the treatment of metastatic HR positive breast cancer in clinical stage Ib/II.
In addition, Lilly's LY-2835219 is also in clinical stage III study. If these clinical trials can achieve the desired results, CDK4/CDK6 dual inhibitor will bring a large number of patients with advanced breast cancer more survival benefits.
As mentioned above, the development of CDK4/CDK6 selective dual inhibitor has become a frontier and focus area for anti-tumor drug research. Therefore, there is an urgent need to develop new CDK kinase inhibitors.